Manufacture of biguanide derivatives



Patented May 23, 1950 MANUFACTURE OF B1GUANIDE, DERIVATIVES Albert Erederick, Crowther, Francis Henry Swinden Curd, and. Francis Leslie Rose, Blackley, Manchester, England, assignors to Imperial Chemical Industries Limited, .a corporation of Great Britain No Drawing. Applieation January 22-, 1948, -Se-- rial No. 3,816.; 'In Great "BritainFebruai-y 1,

4 Claims.

This invention relates to thernanufactureoi biguanide derivatives and more ,particularly it relates to the manufacture of biguanide derivatives which have antimalarial properties.

According to the "invention we manufacture biguanide derivatives which have antimalarial properties by a process which comprisessubjecting ,to'the action of halogenating agents a substance of the formula wherein A represents a benzene nucleuswhich may optionally bear a halogen, lower-alkyl or lower alkoxy substituent or substituents-in position meta to the NH-' group, wherein X and Y represent hydrogen or-lower alkyl radicals provided both be not lower alkyl radicals at the same time, wherein fR represents a lower alkylradical, R represents hydrogen or a lower alkyl radical, and wherein R and 'R' together containmore than one and fewer than eight carbon atomsn As substances of the stated formula there may be used for example N -phenyl-N -isopropylbi-- guanide (M. P. of monohydrochloride 235--6 0.),

mon hydrochloride 2391.244 ;N pheny1-N -isopropy1bi uanide (M- ;P... .0 drochloride 225 Cr), *N -m-brornoph y1-N r-1I propylbiguanide (M. P. of monohydrochloride 19415" 0.), N -m-bromophenyleN reth-ylbi uae;

nide (M. P. ofmonohydrochloride12164916.),N r-

m-methylpheny1-N -isopropylbiguanide M. of,

monohydrochloride 216 G.) ,rNleme-clflorophenyl- N methyl N -is0propy1biguanide 4M. of

monohydrochloride l37+g8- 0.) and N -m-methe oxyphenyl N isopropy-l'biguanide (M. P. :of monohydrochloride 212-13 6.?

These starting materials may-' be obtained, in.

V where N or N bear alkyl substituents-the start- ,1

ins ma erials ma be made 'fQl e em br the proce s described i -pensl ns ap lie tien eri No 7 9, 6 new eb ndon da f Birtwel e -elt' fi edflenuary 3 viz, by-inter etieme an apn epr e .am ne-eempeund with an entree. suany eurea or S a ky uanrl e eur e; heepmp unds whe e Xend both-hy ra. sen may of c urse lse be ma e b t is r ee Equally the product oi the proce o t is vention ma also, where. Xend Y are both hy ra-- gen, be mad for example, by h ce ses of British Patent No. 577,843, or, where or ;Y is a l wer alkyl radica for example b th reeess pfc,o -pen ding application Serial No. 720 09 6, now abandoned, of Birtwell ,et a1. filed Jane; uary 3, 1 h present p oc p ov des n ea y n e n en ent way of a n the para-halogen substituted 'b suani e rom these which are unsubstituted in that position. The process of British specification No. 577,843 requires as in ima sta tin materie e he ee nated a ylam ne wh c n man ea m y bei fi cu of e s In the e e e it ma e mere convenien t uild u t ie eni mele lile and then finally haiogenate as in the process f: the present invention. lialp enation, according to the prgeess of the invention, of unsubstituted. or m ta-subst tut d p n bisuen res lts pararsubstitution andin little or-no substitution, in the ent re-p si ion .Me v th rhen b lguanides bearing ortho-halogen substituents are r a ve y ittle acti e es-en mele elen som cases where there is formed simultaneously a small proportion of the less active ortho- ,substi ut on-pr d this a be d fi ult to sepa at fromthe desired highly aetive, paras-substituted preduet- H wever th re en e f e sm l e e: po on of inact e har le s S s ance e serious detriment to the use of the product as: an ant mala ia a ent,- .7

It s surpris n that t e helesenatien pres a of this invention nan ,be carried out smoothl and l adi t he para-halo en su stitu ed product in good y eld I woul h ve ee X-- acid, nitrobenzene, concentrated sulphuric acid. The invention is illustrated but not limited by the following examples in which the parts are by weight.

Example 1 2.56 parts of N -phenyl-N -isopropylbiguanide hydrochloride are dissolved in water, the solution is made alkaline by addition of sodium hydroxide, and is then extracted with benzene. The benzene extract is dried with anhydrous potassium carbonate, filtered and evaporated to dryness. The N -phenyl-N -isopropylbiguanide, so obtained, is dissolved in 10 parts of glacial acetic acid and chlorine gas is passed into the solution at -10 C. until 0.71 part of chlorine has been absorbed. The reaction mixture is then allowed to stand at room temperature for one hour and is diluted with 40 parts of water, clarifled with decolourising carbon and poured into an excess of a 20% aqueous sodium hydroxide solution. The precipitated solid is separated and dissolved in 30 parts of 7% hydrochloric acid. The solution is made just alkaline to Brilliant Yellow and the crystalline solid which separates is filtered oil and recrystallised from water. There is thus obtained N -p-chlorophenyl-N -isopropylbiguanide hydrochloride, M. P. 236 C. N -pchlorophenyl-N -isopropylbiguanide acetate, M. P. 183-1835 0., is obtained when the hydrochloride is converted to the base which is then dissolved in dry ethyl acetate and treated with glacial acetic acid. a

By the process described in this example, using an appropriate starting material, there may also be made N -p-chlorophenyl-N -ethylbiguanide (M. P. 113-114 C., M. P. of acetate l60161 C.) and N p chlorophenyl N -n-propylbiguanide (M. P. 58.5-60 0., M. P. of acetate 164-165 0.).

Example 2 The base obtained from 2.56 parts of N -phenyl-N -isopropylbiguanide hydrochloride is dissolved in 36 parts of 98% sulphuric acid and the solution is stirred at room temperature for 16 hours with 1.6 parts of bromine. The product is poured into 100 parts of water and the mixture is clarified with decolourising carbon and poured into an excess of 40% aqeous sodium hydroxide solution. The solid which separates is filtered ofi', washed with water, dissolved in 50 parts of 7% hydrochloric acid and filtered. The filtrate is made just alkaline to Brilliant Yellow by addition of aqueous ammonia. The solid which separates is filtered off, washed with water, dried and crystallised from a mixture of ethanol and ethyl acetate. The crystals so formed consist of N -p-bromophenyl-N -isopropylbiguanide hydrochloride and have M. P. 241 C.

By the process described in this example, using an' appropriate starting material, there may also be obtained N -p-bromopheny1-N -n-propylbiguanide (M. P. of monohydrochloride 221-222 C.) and N -p -bromophenyl-N -ethylbiguanide (M. P. of monohydrochloride 233-234 0.).

Example 3 1.28 parts of N -phenyl-N -isopropylbiguanide hydrochloride are converted to the base and the base is dissolved in 8 parts of glacial acetic acid. A solution of 0.89 part of iodine monochloride in 2.6 parts of glacial acetic acid is added and the mixture is heated at 100 C. for 8 hours. The reaction mixture is poured into 50 parts of water and the mixture is extracted with benzene. The

aqueous layer after extraction is poured into an excess of 40% sodium hydroxide solution and the oil which separates is extracted with benzene. The benzene solution is shaken with 25 parts of 7% hydrochloric acid in 3portions' and the aqueous portions are combined, clarified and made just alkaline to Brilliant Yellow by addition of aqueous ammonia. The precipitated solid is filtered off, washed with water and crystallised from water giving small, colourless needles which consists of N -p-iodophenyl-N -isopropylbiguanide hydrochloride and have M. P. 236 C.

By the, process described in this example, using an appropriate starting material, there may also be made N -p-iodophenyl-N -n-propylbiguanide (M. P. of monohydrochloride ZZZ-224 0.); and N -p-iodophenyl-N -ethylbiguanide (M. P. of monohydrochloride 239-240 C.)

Example 4 The base obtained from 2.5 parts of N -phenyl N -methyl-N -isopropylbiguanide hydrochloride is dissolved in 10 parts of glacial acetic acid and chlorine gas is passed into the solution at 20 C. until 0.65 part of chlorine has been absorbed. The mixture is allowed to stand at 20 C. for one hour and is then diluted. with 30 parts. of water, clarified and poured into an excess of ice cold 40% sodium hydroxide solution. The solid which is precipitated is filtered off, washed with water and dried in vacuo over sodium hydroxide. The dry baseis treated with 0.55 part of glacial acetic acid and the mixture is diluted with ethyl acetate. The solid is filtered off and crystallised from a mixture of methanol and ethyl acetate to give N -pchlorophenyl-N -methyl- N -isopropylbiguanide acetate, of M. P. 215 C.

By the process described in this example, using an appropriate starting material, there may also be made N -p-chlorophenyl-N -methyl-N n-propylbiguanide (M. P. -126 C.) and N -pchlorophenyl-N :N -diethy1biguanide (M. P. 133- 134 C.)

Example 5 The base obtained from 1.35 parts of N -phenyl N -methyl-N -isopropylbiguanide hydrochloride is dissolved in 5 parts of glacial acetic acid and is treated with 0.8 part of bromine dissolved in 4 parts of glacial acetic acid. The mixture is allowed to stand at room temperature for 1 hour and then diluted with 20 parts of water and made strongly alkaline by addition of sodium hydroxide. The solid matter is filtered off, washed with a little water and dissolved in 1.0 parts of 7% hydrochloric acid. The solution is clarified and made just alkaline to Brilliant Yellow by addition of aqueousammonia. The solid which separates is filtered off, washed with water and crystallised from water. Colourless needles of N -p-bromophenyl-N -methyl-N -isopropylbiguanide hydrochloride, with M. P. 243 C., are thus obtained.

By the process described in this example, using an appropriate starting material, there may also be made N p bromophenyl-N -methyl-N -npropylbiguanide (M. P. of monohydrochloride 237 C.) and N -p-bromophenyl-N :N -diethylbiguanide (M. P. -141 0.).

Example 6 1.35 parts of N -phenyl-N -methyl-N -isopropylbiguanide hydrochloride are, converted to the base, the base is dissolved in '7' parts of glacial acetic acid and there is added a solution of 0.8 part of iodine monochloride in.2.3 parts of glaazaisoezsve n-propylbiguani'de (M. P. of monohydrochloride 238 C.)

Example 7 1.27.";parts of Ni phenyl N%-isopr.opylbiguanide hydrochloride are dissolved in 10 parts of glacial adeti'ciacidiandrchlorine gas is passedrinto the :1solution= 'until 0 .3.7 'part'zof chlorine. has "been absorbed: The mixtureds'allowed to Sstand. at atmimospherictemperature for one:hour. *It-is then 1 treated asiis described-cini Example '3; and 'there are-obtained colourless-crystals"from water of N -pachlorophenyl-N-isopropylbiguanide hydrochloride, M. P. 236 '0.

"Example 8 Q 17.73 parts of N -ni chl0r0plienyLNQ-isopropyl-bigu'ani'de are dissolved in 110'parts of glacial acetic acid. To this solution, cooled and agitated, are added 58 parts of-- glacial acetic acid containing 5.0. parts.of chlorine. -.The mixture is allowed to warm .to atmospheric temperature and is then allowed to stand for 17 hours. It is then treated as is described in Example 3 and afterrepeated crystallisation froml water there are. obtained colourless crystals 'ofiNl-3z4 dichlo- 1 rophenyl-N -isopropylbiguanide 1 hydrochloride,

M. P. 239 C.

By theprocess described in thisiexamplansing an appropriatestarting mater-iahrthere may also be obtained- N -Bi4 dichlorophenyl-N =n-prolL-pylbiguanide (M.-P;1of monohydrochloride 237-8 N -3 4sdichlorophenyl-a'Nfiemethyl+N -iso- .propylbigu'anide (M. 'P. :of monohydrochloride,

251-2 C.) :Nl-3 i 4edichlorophen'yl+N -methyl-N n-pzopylbiguanide (MtP. 40f monohydrochloride, 236 C.) N -3 ii-dichlorophenyl-N -.ethylbigua- ,anide. (M. Piiof;mono'hydrochloride 2l6..C. N

4 tdichlorophenyl-N i N. diethylbiguanide (i I. .:,.of; monohydrochloride 231.? C.)-, N -3zz5-tr'ichlorophenyl-N -isopropylbiguanide (M. P. of .--'monohydrochloride- 254-5 Cc) NleS :4 fi-trichlo- .rophenyl-l l5;n+.propylbiguanide (-M. P;oi.-mono- 3 glacial acetic acidl The-mixturelis-allowed to hydrochloride 228-9" co andtNl-3 :4z5atrichlorqphenyl-N -methy1-N -isopropylbiguanide (M. P. ofmonohydrochloride 234-235.? C.) I

J 1 Example 9 As described in Example 8 but using 10.6 parts -oi: bromine in place of the chlorine of Example 8 there is obtained a-colourlesscrystalline product bromophenyl-N5-iso propylbiguanide hydrochloride.

By a similar process, using an appropriate starting material, there may also be obtained N 3-chloro-4-bromophenyl-N -ethylbiguanide (M. P. of monohydrochloride 217 C.) N -3-chloro-4- bromophenyl-N -n-propylbiguanide (M. P. of monohydrochloride 217 C.) N 3 chloro-4- bromophenyl-N -methy1-N isopropylbiguanide (M. P. of monohydrochloride 244 C.) and N -3- chloroA-bromophenyl-N -methyl-N -n propylbiguanide (M. P. of monohydrochloride 234 C.)

iz'z'zmmple 10 ,biguanidehydriochloride are convefrted'to the free baseJafid-this. basefis dissolved Tin 301parts of glacial aceticj'acid. ..A solution of 3.6 parts of iodine monochloridein 14 parts of glacial acetic acid. is added and the mixture is heated at 100 '5 IO. for Tl7.hours; It'isth'en treated as is de- .',scribed.-'in Example '3., There are thus obtained colourless crystals, .from Water, of'"N 3.-'-chloro-4- iodophenyl N5-isopropy1biguanide;hydrochloride, iMI'P. 221-222" C.

By the process described in this example, using an appropriate starting'materi'al there; may also. be obtaiii'e'd'NlQ-chloroa-4eio'dophenyl N -n- .propylbiguanide (M. P. .of monohydrochloride "225 CD"; 'N -3-chloro-4-iodopl'ienyl-1N:methyl- N -isopropylbiguanide (M. P. of monohydrochloride 231 C.) N -3ashloroeA-iodophenfl-N -methyl-N-n-propy1big-uanide. (M. P. of monohydrochloride. 229-23.0 C.).. and .Nl'-3=chloro.:.4..iodophenyl-N -ethylbiguanide (M. P... .of. monohydrochloride 226-227.. C.)

-..,.-.. q ple 11 6.69 parts of N em-bromophenyleNi-isopropylbiguanide hydrochloride are dissolved ini70 parts .of; glacialacetic acid. Chlorine gas is passedinto the mixture at-roomtemperature until 1.42.parts of chlorine havabee'n abs0rbed..-..The. mixture is allowed to stand for '20 hours at atmospheric temperature andis-*then-treated as is described 'in: Example 5;- There is thus obtainedna colourless crystalline product which. consists-substan- .tially .-of- N -4-chloro-3 bromophenyl-Nfi =isopropylbiguanide.

' By the-process describedin this example, usa ing an appropriate starting materiahthere may also. be obtained :N -4==chloro-3=bromophenyl-N Q n-propylbig.uanide M. P..ofLrmonohydrochloride 1978, C.) ,-N a4-chloro-3 bromophenyl-N-;ethyl biguanide (M. P. of monohydrochloride. 215-6 .C.-), N 41-chloro-3-bromophenyl-N5rmethylN .isopropylbiguanide. (Mr-P. of monohydrochloride 5 240-24? 0.) and N -fii-chloro-3-bromophenyl-N ,methyl-N -n-propy1biguanide (M. Poofmonohy- I drochloride- 232-2325 C.)

Example 12 4.33 parts of N -m-bromophenyl-N -isopropylbiguanide. arexdissolved in 38 parts (if-glacial acetic acid and thereis added;- with-cooling, a solution of 2.32:parts'of-bromine) in 13.8 parts of 59. stand: atatmospheric temperature for-r24 hours.

. ltis then treated as is described iniExample 3.

- There are thus obtained colourless-prisms which f consist. substantially :of. fN -3 e-dibromophenyl- Ni-isopropylbiguanide hydrochloride.

5 :By the" process-described -in this example,- using anappropriate starting material. there may 1- .1 y 5., which consists substantially of N -3-chloro-4- also be obtamed N 3 dlbromophenyl N n propylbiguanide (M. -P. ofmonbhydrochloride '2l7.5-219 C.) ,-IN -3 4-dibrorhophe'nyl-N -ethylbiguanide (M. P. of monohydrochloride 213-21? C.) N -3 4-dibromophenyl-N -methylN -isopropylbiguanide (M. P. of monohydrochloride 234- 235 C.), and N -3:4-dibromophenyl-N -methyl- 7 N -n-propylbiguanide (M. P. of monohydrochloride 234-235" C.).

Example 13 The base obtained from 3.4 parts of N -mbromopheny1-N -isopropylbiguanide hydrochloride is dissolved in 13 parts of glacial acid and,

there is added a solutionof 1.62 parts of iodine monochloride in parts of glacial acetic acid. The mixture is heated at 100 C. for 46 hours and is then treated as is described in Example 3. There are thus obtained colourless crystals which consist substantially of N -3-bromo-4iodopheny1- N -isopropylbiguanide hydrochloride.

By the process described in this example, using an appropriate starting material, there may also be obtained N -3-bromo-4-iodophenyl-N -methyl-N -isopropylbiguanide (M. P. of monohydrochloride 232-233 C.) N -3-bromo-4-iodophenyl- N -methyl-N -n-propylbiguanide (M. P. of monohydrochloride 228-9 0.), N -3-bromo-4-iodopheny1-N -n-propylbiguanide (M. P. of monohydrochloride 227-8 C.), N -3br0mo-4-iodophenyl-N -ethylbiguanide (M. P. of monohydrochloride 220-1 0.).

Example 14 6.49 parts of N -3:5-dichlorophenyl-N -isopropylbiguanide hydrochloride are dissolved in 40 parts of glacial acetic acid and there is added a solution of 3.36 parts of bromine in 15 parts of glacial acetic acid. The mixture is heated at 60 C. for 5 hours and is then allowed to stand at atmospheric temperature for 16 hours. It is then treated as is described in Exampl 5. There are thus obtained colourless needles from water of N -3 5-dichloro-4-bromophenyl N -isopropy1biguan'ide hydrochloride, M. P. 244-5 C.

Example 15 A solution of 10 parts of N -m-tolyl-N -isopropylbiguanide hydrochloride in 75 parts of glacial acetic acid is cooled to 10 C. and a stream of chlorine gas is passed through the solution until 2.79 parts of chlorine have been absorbed. The mixture is allowed to warm to atmospheric ternperature during 2 hours and is then poured into a mixture of 150 parts of 40% aqueous sodium hydroxide solution and 1000 parts of water. The precipitated solid is filtered off, washed with water and dried. Crystallisation first from a mixture of benzene and petroleum ether (B. P. 80-100 C.) and then repeated crystallisation from petroleum ether (B. P. 80100 0.) gives N l-chloro- 3- methylphenyl- N -isopr0py1biguanide, M. P. 133-134" 0.

Example 16 'washed with water and then dissolved in 3% aqueous hydrochloric acid. The solution is filtered and then made faintly alkaline to Brilliant Yellow by addition of aqueous ammonia solution. The precipitated solid is separated and dried.

' It is then recrystallised from a mixture of ethanol r and 100 parts of water.

and ethyl acetate to give N -3z4-dichlorophenyl- N -methyl-N -isopropylbiguanide hydrochloride, M. P. 165-166 C.

Example 17 2.59 parts of N -m-methoxyphenyl-N -isopropylbiguanide hydrochloride are dissolved in 50 parts of glacial acetic acid. The solution is cooled to 10-15 C. and 0.71 part of chlorine gas is passed into it. The solution is allowed to stand at atmospheric temperature for 4 hours and is then poured into a cooled mixture of parts of 40% aqueous sodium hydroxide solution The precipitated solid is filtered off, washed with water, and dissolved in 20 parts of 7% aqueous hydrochloric acid. The solution is filtered and made faintly alkaline to Brilliant Yellow with aqueous ammonia solution. The solid is filtered off, washed with water and crystallised from water. There are thus obtained colourless needles of N -l-chloro- 3-' methoxyphenyl-N -isopropylbiguanide hydrochloride, M. P. 232-233C.

We claim:

1. A process for the manufacture of halogenconta'ining biguanides which comprises subjecting a substance of the general formula:

alk

wherein R and R represent a. radical from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; X and Y represent a radical from the group consisting of hydrogen and lower alkyl radicals with X and Y not being both lower alkyl radicals at the same time; alk represents a lower alkyl radical, and R" represents a radical from the group consisting of hydrogen and lower alkyl, the sum of the carbon atoms in the radicals alk and R being more than one and less than eight, to the action of a halogenating agent from the group consisting of chlorine, bromine and iodine monochloride.

2. A process as claimed in claim 1, wherein said halogenating agent is chlorine and the reaction is carried out at a temperature between 0 and 20 C.

3. A process as claimed in claim 1, wherein said halogenating agent is bromine and the reaction is carried out at a temperature between room temperature and 60 C.

4. A process as claimed in claim 1, wherein said halogenating agent is iodine monochloride and le reaction is carried out at a temperature of C.

ALBERT FREDERICK CROWTHER. FRANCIS HENRY SWINDEN CURD. FRANCIS LESLIE ROSE.

No references cited. 

1. A PROCESS FOR THE MANUFACTURE OF HALOGENCONTAINING BIGUANIDES WHICH COMPRISES SUBJECTING A SUBSTANCE OF THE GENERAL FORMULA: 